Leukocytes occurring in normal human peripheral blood comprise granulocytes, monocytes and lymphocytes, and granulocytes are further divided into neutrophils, eosinophils, and basophils. In the production of these blood cells, myelocytic stem cells and lymphatic stem cells differentiate from common undifferentiated hematopoietic stem cells, and from these stem cells, finally, each line of leukocytes differentiates. Blood cell-related cells including these hematopoietic stem cells are also referred to as hematopoietic cells. Tumors (hematopoietic tumors) of hematopoietic cells include leukemia, lymphoma, myeloma, and the like.
Leukemia is a disease of cancerated hematopoietic cells, in which bone marrow is occupied by leukemic cells and thereby normal hematopoietic functions are inhibited, resulting in the decreased production of normal blood cells and in subsequent development of anemia, leukopenia and thrombocytopenia. Also, based on the origin of leukemic cells, leukemia is roughly divided into two types: myelocytic leukemia and lymphocytic leukemia, each of which is further divided into the acute form and the chronic form. Furthermore, as a subtype, mixed lineage leukemia having cellular traits of the two lineages, bone marrow lineage and lymphocyte lineage, is also known.
Tumorigenesis takes place at the level of hematopoietic stem cells, wherein there are a case in which differentiation stops at a certain stage of differentiation and maturation and tumors are only formed in the cells upstream thereof, and a case in which the functions of differentiation and maturation are retained though it evades the biological regulatory functions and exhibits autonomous growth. The former includes acute leukemia, and the latter includes chronic leukemia and the myelodysplastic syndrome. Based on the identity of the growing cells, acute leukemia is roughly divided into acute myelocytic leukemia (AML), acute monocytic leukemia (AMoL), acute erythroleukemia, megakaryobalastic leukemia, and acute lymphocytic leukemia (ALL).
As a subtype, acute promyelocytic leukemia (APL) is known. Acute leukemia and the myelodysplastic syndrome may be classified based on the French-American-British classification (FAB classification). In the FAB classification, acute lymphocytic leukemia is divided into L1, L2, and L3, and for example Burkitt's lymphoma is classified into L3. Acute myelocytic leukemia is divided into M0, M1, M2, M3, M4, M5, M6, and M7 and, for example, erythrocyte abnormality is classified into M6 and megakaryobalastic leukemia is classified into M7. These methods of classification and of testing are known and are described in many textbooks (for example, Shin-Rinsho Naikagaku (New Clinical Internal Medicine), Fumimaro Takaku and Etsuro Ogata, Igakushoin Ltd., 1999).
Also, based on the identity of growing cells, chronic leukemia is roughly divided into chronic myelocytic leukemia (CML) and chronic lymphocytic leukemia (CLL). Also, as a subtype of chronic myelocytic leukemia, chronic myelomonocytic leukemia is known, and as a subtype of chronic lymphocytic leukemia, prolymphocytic leukemia is known.
Lymphoma is a generic term for tumors derived from cells constituting lymphatic tissues such as the lymph node, and is hematopoietic cell tumors caused mainly by canceration of lymphocytes. Malignant lymphoma is divided into Hodgkin's disease and non-Hodgkin lymphoma, both of which are cancerated lymphocytic cells and can be divided into the T lymphocytic and the B lymphocytic types.
As non-Hodgkin lymphoma, there are known B lymphocytic tumors such as follicular lymphoma, mantle cell lymphoma, Burkitt's lymphoma, pre-B lymphoma and the like. For T lymphocytic tumors, there are known adult T cell leukemia (ATL) and peripheral non-ATL T-lymphoma (PNTL). Also, diffuse lymphoma comprising two types (T lymphocytic and B lymphocytic) is included in non-Hodgkin lymphoma. Furthermore, as a subtype, hairy cell leukemia which is a B lymphocytic tumor is known.
Lymphocytic leukemia and lymphoma which are canceration of major constituent cells of lymphocytes are referred to as lymphocytic tumors, and are roughly divided into B lymphocytic tumors and T lymphocytic tumors. For example, B lymphocytic tumors include acute B lymphocytic leukemia (B-ALL), chronic B lymphocytic leukemia (B-CLL), pre-B lymphoma, Burkitt's lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse lymphoma and the like. T lymphocytic tumors include acute T lymphocytic leukemia (T-ALL), chronic T lymphocytic leukemia (T-CLL), adult T cell leukemia (ATL), peripheral non-ATL T-lymphoma (PNTL) and the like (Zukai Rinshogan series (Illustrated Clinical Cancer Series) No. 17, Leukemia and lymphoma, Takashi Sugimura et al., MEDICAL VIEW Co., Ltd., 1987; B Lymphocytic Tumors, Kiyoshi Takatsuki, Nishimura Co.,Ltd., 1991; Shin-Rinsho Naikagaku (New Clinical Internal Medicine), Fumimaro Takaku and Etsuro Ogata, Igakushoin Ltd., 1999). Myeloma is also a type of lymphatic tumor, and exhibits characteristic clinical findings.
Myeloma which is also referred to as plasmacytoma and multiple myeloma is a neoplastic disease characterized by the accumulation of monoclonal plasma cells in the bone marrow. Myeloma is a disease in which plasma cells, i.e. terminally differentiated B cells that produce and secrete immunoglobulins, are monoclonally increased mainly in the bone marrow, and thus in the serum of patients with this disease, monoclonal immunoglobulins or components thereof, L chain, H chain, etc., can be detected.
For the treatment of myeloma, chemotherapeutic agents etc. have been used so far, but no effective therapeutic agents have been found that lead to the complete remission and the extension of the survival of patients. Thus, there has been a long-awaited need for agents having therapeutic effects based on a new mechanism of action. For lymphoma and leukemia as well, though moderately effective chemotherapy has been developed, new agents have been waited for due to adverse reactions.
On the other hand, Goto, T. et al. have reported a monoclonal antibody (mouse anti-HM1.24 antibody) that was obtained by immunizing mice with human plasma cells (Blood (1994) 84, 1922-1930). When anti-HM1.24 antibody was administered to a mouse transplanted with human myeloma cells, the antibody accumulated in tumor tissues in a specific manner (Masaaki Kosaka et al., Nippon Rinsho (Japan Clinical) (1995) 53, 627-635), suggesting that anti-HM1.24 antibody could be applied in the diagnosis of tumor localization by radioisotopic labeling, missile therapies such as radiotherapy, and the like.
In the above Blood (1994) 84, 1922-1930, it has been described that anti-HM1.24 antibody has an in vitro cytotoxicity on a human myeloma cell line RPMI8226. It has also been shown that chimeric anti-HM1.24 antibody, or anti-HM1.24 antibody that is mouse anti-HM1.24 antibody rendered chimeric, and a humanized reshaped anti-HM1.24 antibody, specifically bind to myeloma cells and have cytotoxicity (Blood (1999) 93, 3922-3920).
On the other hand, it has also been demonstrated for lymphocytic tumors that an antigen protein recognized by anti-HM1.24 antibody is expressed in lymphocytic tumors, and that anti-HM1.24 antibody has a cytotoxicity on lymphocytic tumors due to a CDC activity and an ADCC activity, and thereby exhibits anti-tumor effect (WO 98/35698). Thus, HM1.24 antigen has been highly expressed not only in myeloma cells that are terminally differentiated B cells but also in lymphocytic tumors, and anti-HM1.24 antibody that recognizes HM1.24 antigen is useful as a therapeutic agent for lymphocytic tumors.
Thus, HM1.24 antigen has been highly expressed in myeloma cells that are terminally differentiated B cells and in lymphocytic tumors, and anti-HM1.24 antibody that recognizes this antigen exhibits cell-killing activity in proportion to the number of HM1.24 antigens on the cell surface, and thus immunotherapy with anti-HM1.24 antibody is expected to provide an effective method of treating multiple myeloma and lymphocytic tumors. Thus, if the amount of HM1.24 antigen, which is an antigen against anti-HM1.24 antibody, expressed on the cell surface could be enhanced, the administration of a smaller amount of the antibody is expected to provide equivalent cytotoxicity, and it would become possible to decrease adverse reactions.
Furthermore, for hematopoietic tumor cells that are not expressing HM1.24 antigen, if the amount of HM1.24 antigen expressed on the cell surface could be enhanced, cytotoxicity or cytocidal effect through ADCC activity or CDC activity with anti-HM1.24 antibody is expected for hematopoietic tumor cells for which, generally, anti-HM1.24 antibody alone is not effective.
On the other hand, interferon, that was discovered as a substance having an activity of inhibiting viral growth, is currently known to be classified into four groups of α, β, γ, and ω in mammals, and to have a variety of biological activities (Pestka, S., et al., Ann. Rev. Biochem. (1987) 56, 727-777; Langer, J. A., et al., Immunology Today (1988) 9, 393-400). However, there were no reports on whether interferon α and interferon γ could have an effect of increasing the expressed amount of HM1.24 antigen in myeloma cells or cells of hematopoietic tumors such as lymphocytic tumors.
On the other hand, interferon regulatory factor (IRF)-1 and 2 were identified as a transcription regulatory factor of the IFN-β gene. IRF-1 and 2 are generally known to bind to the same gene regulatory sequence, and act in an antagonistic manner in that IRF-1 acs as a transcription activation factor and IRF-2 as a transcription suppressing factor. The NIH3T3 cells in which IRF-2 was highly expressed has been demonstrated to exhibit enhanced cell saturation density, colony formation in the methylcellulose gel, and a tumorigenic property in nude mice, and IRF-2 has been shown to act as an oncogene.
On the other hand, recent advances in research have indicated that IRF-2 is required for the expression of histone H4 that acts in the control of cell cycle. IRF-2 has also been shown to increase the expression of vascular cell adhesion molecule-1 (VCAM-1) in muscle cells, and it has also been demonstrated that the acid region (182 to 218) of IRF-2 is involved in the activation of VCAM-1. Based on this, it is known that IRF-2 not only acts as a transcription regulatory factor but may act as a transcription activation factor.
However, it was not known that the IRF-2 protein binds to the promoter (HM1.24 promoter) of the HM1.24 antigen gene, and activates said promoter.